Abstract

Background Focality of onset of amyotrophic lateral sclerosis (ALS) is not understood. Attempts to implicate physical exercise in the
aetiology of ALS have provided inconsistent results. If physical use of a limb were important in defining the site of onset,
then handedness might be expected to influence the side of upper limb-onset disease and footedness likewise in lower limb-onset
ALS.

Methods ALS patients registered with an internet-based support site were invited to complete an online questionnaire concerning site
of onset of symptoms and their dominant hand and foot. A binomial test of proportions was used to investigate the null hypothesis
that handedness and footedness do not influence side of onset in upper and lower limb-onset ALS, respectively.

Results 343 ALS patients with limb-onset disease were studied. For upper limb-onset patients, there was concordance for side of onset
and handedness (64%; p<0.0006). For lower limb-onset patients, concordance for side of onset and footedness was absent. The
frequency of left handedness was commensurate with that found in the general population.

Interpretation These results are potentially consistent with the hypothesis that exercise influences pathogenesis in ALS since routine physical
demands on the upper limb are heavily influenced by limb dominance, whereas in the lower limbs the commonest function is standing
or locomotion, which uses both legs equally. However, there may also be an inherent cortical vulnerability underlying upper
limb-onset laterality, possibly influenced by changes in neuronal connectivity and cortical excitability in relation to handedness
and reflected by the “split hand” phenomenon consistently observed in ALS.

Footnotes

Funding MRT is supported by the MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellowship. PW, CAB, and MPM are employees of PatientsLikeMe
and own stock options in the company. PatientsLikeMe receives research support from UCB, Novartis, and Avanir.